{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T12:11:07Z","timestamp":1783685467636,"version":"3.55.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T00:00:00Z","timestamp":1718236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>This case report details the identification of a novel likely pathogenic splicing variant in the TTN gene, associated with dilated cardiomyopathy (DCM), in a 42-year-old male patient presenting with early-onset heart failure and reduced ejection fraction. DCM is a nonischemic heart condition characterized by left biventricular dilation and systolic dysfunction, with approximately one-third of cases being familial and often linked to genetic mutations. The TTN gene, encoding the largest human protein essential for muscle contraction and sarcomere structure, is implicated in about 25% of DCM cases through mutations, especially truncating variants. Our investigation revealed a previously unreported G\u2009&amp;gt;\u2009C mutation at the splice acceptor site in intron 356 of TTN, confirmed by Sanger sequencing and not found in population databases, suggesting a novel contribution to the understanding of DCM etiology. The case emphasizes the critical role of the TTN gene in cardiac function and the genetic complexity underlying DCM. A comprehensive literature review highlighted the prevalence and significance of splice variants in the TTN gene, particularly those affecting the titin A-band, which is known for its role in muscle contraction and stability. This variant's identification underscores the importance of genetic screening in patients with DCM, offering insights into the disease's familial transmission and potential therapeutic targets. Our findings contribute to the expanding knowledge of genetic factors in DCM, demonstrating the necessity of integrating genetic diagnostics in cardiovascular medicine. This case supports the growing evidence linking splicing mutations in specific regions of the TTN gene to DCM development and underscores the importance of genetic counseling and testing in managing heart disease.<\/jats:p>","DOI":"10.3389\/fcvm.2024.1387063","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T14:00:43Z","timestamp":1718287243000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["TTN novel splice variant in familial dilated cardiomyopathy and splice variants review: a case report"],"prefix":"10.3389","volume":"11","author":[{"given":"Paul","family":"Le\u00f3n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Hinojosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Torres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Moreano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa I.","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41572-019-0084-1","article-title":"Dilated cardiomyopathy","volume":"5","author":"Schultheiss","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/s41569-019-0284-0","article-title":"Genetics of dilated cardiomyopathy: practical implications for heart failure management","volume":"17","author":"Rosenbaum","year":"2020","journal-title":"Nat Rev Cardiol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.ppedcard.2014.10.003","article-title":"Genetic causes of dilated cardiomyopathy","volume":"37","author":"Mestroni","year":"2014","journal-title":"Prog Pediatr Cardiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1097\/GIM.0b013e3181f2481f","article-title":"Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals","volume":"12","author":"Hershberger","year":"2010","journal-title":"Genet Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.cardfail.2018.03.004","article-title":"Genetic evaluation of cardiomyopathy-A heart failure society of America practice guideline","volume":"24","author":"Hershberger","year":"2018","journal-title":"J Card Fail"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1093\/eurheartj\/ehv727","article-title":"Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases","volume":"37","author":"Pinto","year":"2016","journal-title":"Eur Heart J"},{"key":"B7","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3389\/fcvm.2016.00021","article-title":"A review of the giant protein titin in clinical molecular diagnostics of cardiomyopathies","volume":"3","author":"Gigli","year":"2016","journal-title":"Front Cardiovasc Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.3389\/fphys.2019.01436","article-title":"The giant protein titin\u2019s role in cardiomyopathy: genetic, transcriptional, and post-translational modifications of TTN and their contribution to cardiac disease","volume":"10","author":"Tharp","year":"2019","journal-title":"Front Physiol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.jmoldx.2018.04.001","article-title":"A reliable targeted next-generation sequencing strategy for diagnosis of myopathies and muscular dystrophies, especially for the giant titin and nebulin genes","volume":"20","author":"Zenagui","year":"2018","journal-title":"J Mol Diagn"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e003389","DOI":"10.1161\/CIRCGEN.121.003389","article-title":"Contribution of noncanonical splice variants to TTN truncating variant cardiomyopathy","volume":"14","author":"Patel","year":"2021","journal-title":"Circ Genomic Precis Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e0145284","DOI":"10.1371\/journal.pone.0145284","article-title":"Prevalence of titin truncating variants in general population","volume":"10","author":"Akinrinade","year":"2015","journal-title":"PLoS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.1038\/s41436-020-0914-2","article-title":"Genotype-phenotype correlations in recessive titinopathies","volume":"22","author":"Savarese","year":"2020","journal-title":"Genet Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e0170843","DOI":"10.1371\/journal.pone.0170843","article-title":"Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels","volume":"12","author":"LaDuca","year":"2017","journal-title":"PLoS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e001763","DOI":"10.1161\/CIRCGENETICS.117.001763","article-title":"Novel genetic triggers and genotype-phenotype correlations in patients with left ventricular noncompaction","volume":"10","author":"Miszalski-Jamka","year":"2017","journal-title":"Circ Cardiovasc Genet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"270ra6","DOI":"10.1126\/scitranslmed.3010134","article-title":"Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease","volume":"7","author":"Roberts","year":"2015","journal-title":"Sci Transl Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1017\/cjn.2017.286","article-title":"Next-generation sequencing to diagnose muscular dystrophy, rhabdomyolysis, and HyperCKemia","volume":"45","author":"Wu","year":"2018","journal-title":"Can J Neurol Sci"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e004682","DOI":"10.1161\/CIRCHEARTFAILURE.117.004682","article-title":"Prevalence of pathogenic gene mutations and prognosis do not differ in isolated left ventricular dysfunction compared with dilated cardiomyopathy","volume":"11","author":"Hazebroek","year":"2018","journal-title":"Circ Heart Fail"},{"key":"B18","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1001\/jamacardio.2016.0208","article-title":"Recovery of cardiac function in cardiomyopathy caused by titin truncation","volume":"1","author":"Felkin","year":"2016","journal-title":"JAMA Cardiol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1212\/WNL.0b013e3182a6ca62","article-title":"Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy","volume":"81","author":"Ceyhan-Birsoy","year":"2013","journal-title":"Neurology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3390\/genes12060883","article-title":"The combined human genotype of truncating TTN and RBM20 mutations is associated with severe and early onset of dilated cardiomyopathy","volume":"12","author":"Gaertner","year":"2021","journal-title":"Genes (Basel)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1056\/NEJMoa1505517","article-title":"Shared genetic predisposition in peripartum and dilated cardiomyopathies","volume":"374","author":"Ware","year":"2016","journal-title":"N Engl J Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e173438","DOI":"10.1001\/jamapediatrics.2017.3438","article-title":"Use of exome sequencing for infants in intensive care units: ascertainment of severe single-gene disorders and effect on medical management","volume":"171","author":"Meng","year":"2017","journal-title":"JAMA Pediatr"},{"key":"B23","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/ng.3719","article-title":"Titin-truncating variants affect heart function in disease cohorts and the general population","volume":"49","author":"Schafer","year":"2017","journal-title":"Nat Genet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e14","DOI":"10.1212\/NXG.0000000000000015","article-title":"Expanding genotype\/phenotype of neuromuscular diseases by comprehensive target capture\/NGS","volume":"1","author":"Tian","year":"2015","journal-title":"Neurol Genet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1002\/humu.23938","article-title":"Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy","volume":"41","author":"Bryen","year":"2020","journal-title":"Hum Mutat"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1002\/ana.25241","article-title":"Congenital titinopathy: comprehensive characterization and pathogenic insights","volume":"83","author":"Oates","year":"2018","journal-title":"Ann Neurol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1002\/ejhf.1030","article-title":"The first titin (c.59926\u2009+\u20091G\u2009>\u2009A) founder mutation associated with dilated cardiomyopathy","volume":"20","author":"Hoorntje","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e0189489","DOI":"10.1371\/journal.pone.0189489","article-title":"High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation","volume":"12","author":"Klauke","year":"2017","journal-title":"PLoS One"},{"key":"B29","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/nature21062","article-title":"Prevalence and architecture of de novo mutations in developmental disorders","volume":"542","year":"2017","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/j.ajhg.2019.01.012","article-title":"Expanding the boundaries of RNA sequencing as a diagnostic tool for rare mendelian disease","volume":"104","author":"Gonorazky","year":"2019","journal-title":"Am J Hum Genet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/ejhg.2016.146","article-title":"Clinical exome sequencing: results from 2,819 samples reflecting 1,000 families","volume":"25","author":"Trujillano","year":"2017","journal-title":"Eur J Hum Genet"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e04478","DOI":"10.1002\/ccr3.4478","article-title":"Centronuclear myopathy due to a de novo nonsense variant and a maternally inherited splice-site variant in TTN: a case report","volume":"9","author":"Huang","year":"2021","journal-title":"Clin Case Rep"},{"key":"B33","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1007\/s00424-019-02272-5","article-title":"Titin mutations and muscle disease","volume":"471","author":"Kellermayer","year":"2019","journal-title":"Pflugers Arch Eur J Physiol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1056\/NEJMoa1110186","article-title":"Truncations of titin causing dilated cardiomyopathy","volume":"366","author":"Herman","year":"2012","journal-title":"N Engl J Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1161\/CIRCRESAHA.116.309396","article-title":"Dilated cardiomyopathy: genetic determinants and mechanisms","volume":"121","author":"McNally","year":"2017","journal-title":"Circ Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1002\/humu.22611","article-title":"A rising titan: TTN review and mutation update","volume":"35","author":"Chauveau","year":"2014","journal-title":"Hum Mutat"},{"key":"B37","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.jjcc.2018.11.001","article-title":"Genetic and non-genetic determinants of clinical phenotypes in cardiomyopathy","volume":"73","author":"Nomura","year":"2019","journal-title":"J Cardiol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1161\/CIRCULATIONAHA.123.064847","article-title":"Rare variant genetics and dilated cardiomyopathy severity: the DCM precision medicine study","volume":"148","author":"Hofmeyer","year":"2023","journal-title":"Circulation"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2024.1387063\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T14:00:46Z","timestamp":1718287246000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2024.1387063\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,13]]},"references-count":38,"alternative-id":["10.3389\/fcvm.2024.1387063"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2024.1387063","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,13]]},"article-number":"1387063"}}